Structure-activity profile of a series of novel triazoloquinazoline adenosine antagonists

Abstract

During a search for benzodiazepine receptor modulators, a highly potent adenosine antagonist (CGS 15943) was discovered. The compound was defined as a resonance-stabilized hybrid of the canonical structures 9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (2a) and 9-chloro-2-(2-furyl)-5,6-dihydro[1,2,4]triazolo[1,5-c]-quinazolin- 5-imine (2b). Spectroscopic evidence and chemical reactivity in polar media favor the amine form 2a as the major contributor of the two canonical structures. The synthesis of 2 and some of its analogues and the structure-activity relationships in four biological test systems are described. Replacement of the 9-chloro group by hydrogen, hydroxyl, or methoxyl gave compounds with comparable binding potency at the A1 and A2 receptors but much less activity as antagonists of 2-chloroadenosine in guinea pig tracheal strips. Alkylation of the 5-amino group caused, in general, a loss of binding activity, particularly at the A2 receptor, as well as complete loss of activity in the tracheal model. Modification of the 2-furyl group caused a pronounced loss of activity in all of the test systems.

A3-adenosine receptors: Design of selective ligands and therapeutic prospects

“…Initially it was found that 2-substituted analogs such as 2-chloroadenosine (14, CADO) and 2-chloro-N 6 -cyclopentyladenosine (11, CCPA) were relatively well tolerated at A 3 receptors (26). For example, CPA (12) and CCPA (11) are equipotent at rat A 3 receptors (Table I). The C2-modification was also compatible or additive with A 3 potency-enhancing modifications at other sites on the adenosine molecule.…”

“…Adenosine agonists, which are almost exclusively derivatives of adenosine (1), have been sought as potential hypotensive (2), antipsychotic (3,4), antiarrhythmic (5), antilipolytic (thus antidiabetic, 6) and cerebroprotective (7)(8)(9)(10) agents. Adenosine antagonists, of which xanthines and a number of fused heterocyclic ring systems are representative (1), have been under development as antiasthmatic (11), antidepressant (12), antiarrhythmic (13), renal protective (14,15), antiparkinson (16) and cognitive enhancing (17)(18)(19) drugs. In spite of the massive effort to develop selective ligands, a number of agents that initially looked promising did not survive clinical trials.…”

Novel therapeutics acting via purine receptors

“…Of these, CGS 15943A, 14 ( Fig. 1) [33], was targeted in aerosol form as an antiasthmatic but failed in development due to skin irritation. A series of triazoloquinoxalines from Pfizer, which for a time were in clinical trials as antidepressants, were later found to include some A 2 -receptor selective adenosine antagonists [34], such as CP 66,713 (15).…”

Regioselective combination of 1,3-dinucleophiles such as 2-mercaptobenzimidazole, 5-mercapto-3-phenyltriazole and potassium thiocyanate with 2,2-dicyanooxiranes

“…7 The synthesis of such compounds has been the subject of several reviews which demonstrate the high importance of this class of compounds. [8][9][10][11][12][13] Considering the importance of these compounds, many methods for the synthesis of these derivatives have been reported successively. The conventional synthesis imidazoles, 17 1,3-oxathioles 18 and condensed imidazolo and thiazolo derivatives, 19 because of their multifunctional structure.…”